A Facile Synthesis of 5-Halopyrimidine-4-Carboxylic Acid Esters via a Minisci Reaction

Abstract

This paper reports the synthesis of various 5-halopyrimidine-4-carboxylic acid esters via the Minisci homolytic alkoxycarbonylation of 5-halopyrimidines. The reaction was found to be highly regioselective, allowing the one-step synthesis of useful amounts (>10 g) of ethyl 5-bromopyrimidine-4-carboxylate where other methods proved difficult. Ethyl 5-bromopyrimidine-4-carboxylate was used for the preparation of potent CK2 inhibitors including CX-5011. This work represents an interesting application of radical chemistry for the preparation of pharmacologically active molecules.

Minisci reaction - alkoxycarbonylation - radicals - pyrimidine - antitumor agents

References and Notes

1 Capdeville RBE. Zimmerman J. Matter A. Nat. Rev. Drug Discovery  2002,  493 

2 Das KCAD. Lewi PJ. Heeres J. de Jonge MR. Koymans LMH. Vinkers HM. Daeyaert F. Ludovici DW. Kukla MJ. De Corte B. Kavash RW. Ho CY. Ye H. Lichtenstein MA. Andries K. Pauwels R. de Bethune M.-P. Boyer PL. Clark P. Hughes SH. Janssen PAJ. Arnold E. J. Med. Chem.  2004,  2550 

3 Stenbuck P, and Hood HM. inventors; US  3049544. 

4 Lednicer D. The Organic Chemistry of Drug Synthesis   Vol. 7:  Wiley-Interscience; Hoboken: 2008.  p.7 

5 Pierre F. O’Brien SE. Haddach M. Bourbon P. Schwaebe MK. Stefan E. Darjania L. Stansfield R. Ho C. Siddiqui-Jain A. Streiner N. Rice WG. Anderes K. Ryckman DM. Bioorg. Med. Chem. Lett.  2011,  21:  1687 

6 Battistutta R. Cozza G. Pierre F. Papinutto E. Lolli G. Sarno S. O’Brien SE. Siddiqui-Jain A. Haddach M. Anderes K. Ryckman DM. Meggio F. Pinna LA. Biochemistry  2011,  50:  8478 

7 Pierre F. Chua PC. O’Brien SE. Siddiqui-Jain A. Bourbon P. Haddach M. Michaux J. Nagasawa J. Schwaebe MK. Stefan E. Vialettes A. Whitten JP. Chen TK. Darjania L. Stansfield R. Anderes K. Bliesath J. Drygin D. Ho C. Omori M. Proffitt C. Streiner N. Trent K. Rice WG. Ryckman DM. J. Med. Chem.  2011,  54:  635 

8 Barreau M, Cotrel C, and Jeanmart C. inventors; US  4110450. 

9 Krasovskiy A. Krasovskaya V. Knochel P. Angew. Chem. Int. Ed.  2006,  45:  2958 

10 Kress TJ. J. Org. Chem.  1979,  44:  2081 

11 Jones CD. Winter MA. Hirsch KS. Stamm N. Taylor HM. Holden HE. Davenport JD. Krumkalns EV. Suhr RG. J. Med. Chem.  1990,  33:  416 

12 Bernardi RCT. Galli R. Minisci F. Perchinunno M. Tetrahedron Lett.  1973,  9:  645 

13 Minisci F. Fontana F. Vismara E. J. Heterocycl. Chem.  1990,  27:  79 

14 Minisci F. Synthesis  1973,  1 

15 Minisci F. Vismara E. Fontana F. Heterocycles  1989,  28:  489 

16 Heinisch G. Lotsch G. Angew. Chem., Int. Ed. Engl.  1985,  24:  692 

17 Yurovskaya MA. Mitkin OD. Chem. Heterocycl. Compd.  1997,  33:  1299 

18 Haider N. Kaferbock J. Heterocycles  2000,  53:  2527 

19 Coppa F. Fontana F. Lazzarini E. Minisci F. Pianese G. Zhao L. Tetrahedron Lett.  1992,  33:  3057 

20 Sakamoto T. Sakasai T. Yamanaka H. Chem. Pharm. Bull.  1980,  28:  571 

21 Phillips OA. Murthy KSK. Fiakpui CY. Knaus EE. Can. J. Chem.  1999,  77:  216 

22 Haider N. Molbank  2002,  M287 

23 Sakamoto T. Ono T. Sakasai T. Yamanaka H. Chem. Pharm. Bull.  1980,  28:  202 

24

Methyl pyruvate typically gave conversions and isolated yields that were inferior (ca. 10-20% lower) to ethyl pyruvate on a variety of tested substrates. This had no practical consequences on the preparation of the target molecule CX-5011, where no significant differences were observed when using the methyl or the ethyl ester as a starting material.

25 Gardini GP. Minisci F. J. Chem. Soc.  1970,  929 

26 Caronna TGG. Minisci F. Chem. Commun.  1969,  201 

27

Typical Procedure for the Synthesis of Ethyl 5-bromo-pyrimidine-4-carboxylate
In a 250 mL round-bottom flask, ethyl pyruvate (4.5 equiv, 50 mL, 450 mmol) was cooled to -10 ˚C. AcOH (70 mL) was added while maintaining the internal temperature below -5 ˚C. A 30% aq H₂O₂ solution (3 equiv, 34 g, 300 mmol) was added dropwise while maintaining the internal temperature below -2 ˚C. In a separate two-neck 2 L round-bottom flask fitted with a mechanical stirrer was charged 5-bromopyrimidine (1.0 equiv, 15.90 g, 100 mmol), toluene (300 mL), and H₂O (70 mL). This solution was cooled to
-10 ˚C, and concentrated H₂SO₄ (3 equiv, 16 mL, 300 mmol) was added followed by FeSO₄˙7H₂O (3.05 equiv, 84.79 g, 305 mmol). To this reaction mixture under vigorous stirring was added the peroxide solution over 1 h, while keeping the internal temperature below 0 ˚C. Once the addition was complete, the reaction mixture was stirred for 30 min and then decanted onto ice water (200 mL). The pH was adjusted to 7 by the addition of 1 N NaOH, and the solution was filtered over a pad of Celite and washed with CH₂Cl₂ (1 L). The aqueous layer was extracted with CH₂Cl₂ (2 × 800 mL). The organics were washed with 5% NaHSO₃ (2 × 500 mL), brine (1.5 L), and then dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (10% EtOAc-hexanes) to give a slightly yellow oil (12.49 g, 54%, >90% pure). Vacuum distillation (bp, 75-76 ˚C, ca. 1 mm Hg) provided analytically pure ethyl 5-bromopyrimidine-4-carboxylate as a clear, colorless oil (11.18 g, 48%). ^¹H NMR (400 MHz, CDCl₃): δ = 9.20 (s, 1 H), 9.00 (s, 1 H), 4.51 (q, J = 7.2 Hz, 2 H), 1.46 (t, J = 7.2 Hz, 3 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 163.2, 161.0, 156.5, 155.8, 117.7, 62.9, 14.0 ppm. LC-MS (ES): >95% pure, m/z 185 [M - OEt]⁺. GC-MS (EI): >99% pure, m/z = 230. The structure of the material was confirmed by its successful use in the next chemical step on route to CX-5011. All other examples described in this paper were prepared with a similar procedure, typically
on a 2-mmol scale. In cases involving poorly soluble pyrimidines, H₂SO₄ was added without external cooling, with the resulting exotherm dissolving the organic substrate. The solution was then cooled to -10 ˚C prior to carrying on the rest of the reaction. Compounds were purified by flash chromatography on silica gel (eluting with 10% EtOAc in hexanes or 2.5% MeOH in CH₂Cl₂) and found to be 95% pure by GC-MS. All compounds isolated were characterized by ^¹H NMR, ^¹³C NMR, and GC-MS.